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Frontiers in veterinary science2022; 9; 963759; doi: 10.3389/fvets.2022.963759

Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells.

Abstract: Tendon injury in the horse carries a high morbidity and monetary burden. Despite appropriate therapy, reinjury is estimated to occur in 50-65% of cases. Although intralesional mesenchymal stem cell (MSC) therapy has improved tissue architecture and reinjury rates, the mechanisms by which they promote repair are still being investigated. Additionally, reevaluating our application of MSCs in tendon injury is necessary given recent evidence that suggests MSCs exposed to inflammation (deemed MSC licensing) have an enhanced reparative effect. However, applying MSC therapy in this context is limited by the inadequate quantification of the temporal cytokine profile in tendon injury, which hinders our ability to administer MSCs into an environment that could potentiate their effect. Therefore, the objectives of this study were to define the temporal cytokine microenvironment in a surgically induced model of equine tendon injury using ultrafiltration probes and subsequently evaluate changes in MSC gene and protein expression following inflammatory licensing with cytokines of similar concentration as identified . In our surgically induced tendon injury model, IL-1β and IL-6 were the predominant pro-inflammatory cytokines present in tendon ultrafiltrate where a discrete peak in cytokine concentration occurred within 48 h following injury. Thereafter, MSCs were licensed with IL-1β and IL-6 at a concentration identified from the study; however, only IL-1β induced upregulation of multiple genes beneficial to tendon healing as identified by RNA-sequencing. Specifically, vascular development, ECM synthesis and remodeling, chemokine and growth factor function alteration, and immunomodulation and tissue reparative genes were significantly upregulated. A significant increase in the protein expression of IL-6, VEGF, and PGE2 was confirmed in IL-1β-licensed MSCs compared to naïve MSCs. This study improves our knowledge of the temporal tendon cytokine microenvironment following injury, which could be beneficial for the development and determining optimal timing of administration of regenerative therapies. Furthermore, these data support the need to further study the benefit of MSCs administered within the inflamed tendon microenvironment or exogenously licensed with IL-1β prior to treatment as licensed MSCs could enhance their therapeutic benefit in the healing tendon.
Copyright © 2022 Koch, Berglund, Messenger, Gilbertie, Ellis and Schnabel.
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Publication Date: 2022-08-11 PubMed ID: 36032300PubMed Central: PMC9410625DOI: 10.3389/fvets.2022.963759Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates how Interleukin-1β (IL-1β) affects mesenchymal stem cells (MSCs) in tendon repair, by enhancing the expression of reparative genes and proteins. Findings suggest exposing MSCs to IL-1β could improve their therapeutic benefit for tendon healing.

Tendon Injury and MSC Therapy

  • Tendon injuries in horses, despite treatment, tend to have a high chance of reinjury, estimated to be between 50-65% of cases. These high rates present increased health risks for the animal and the associated treatment costs constitute a significant financial burden.
  • Currently, intralesional mesenchymal stem cell (MSC) therapy is employed to improve tissue structure and lower reinjury rates. However, the exact mechanisms employed by MSCs to promote repair are still being researched. The study implies the need for continual evaluation of MSC usage in tendon injuries.

Mesenchymal Stem Cell Licensing

  • Recent studies suggest that MSCs exposed to inflammation (also known as MSC licensing) could have increased remedial effects.
  • However, the application of MSC therapy in an inflamed setting has been hindered by a lack of sufficient data regarding the time-specific cytokine profile in tendon injury. Without knowing the cytokine environment, it’s challenging to expose MSCs to an environment that would potentially enhance their effect by inducing inflammation.

Study Objectives and Findings

  • The study’s focal points were to understand more about the cytokine environment in an equine tendon injury and examine changes in MSC gene and protein expressions following inflammatory licensing with these cytokines.
  • In the induced tendon injury study model, Interleukin-1β (IL-1β) and IL-6 were the main pro-inflammatory cytokines. MSCs were exposed to these cytokines, but only IL-1β induced the upregulation of numerous genes that are beneficial to tendon healing, as identified through RNA-sequencing.
  • Particular genes associated with vascular development, extracellular matrix (ECM) synthesis and remodeling, chemokine and growth factor functions, as well as immunomodulation and tissue reparative genes, saw significant upregulation.
  • Additionally, the protein expression of IL-6, Vascular Endothelial Growth Factor (VEGF), and Prostaglandin E2 (PGE2) increased significantly in the MSCs licensed by IL-1β.

Conclusions and Recommendations

  • These findings can enhance the understanding of the cytokine microenvironment in tendon injuries, aiding the development and timing of regenerative therapies.
  • The data strongly indicates a further exploration into the benefits of administering MSCs into the inflamed tendon microenvironment, or licensing them with IL-1β prior to treatment, as these techniques could potentially enhance their therapeutic effect in tendon healing.

Cite This Article

APA
Koch DW, Berglund AK, Messenger KM, Gilbertie JM, Ellis IM, Schnabel LV. (2022). Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells. Front Vet Sci, 9, 963759. https://doi.org/10.3389/fvets.2022.963759

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 963759
PII: 963759

Researcher Affiliations

Koch, Drew W
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Berglund, Alix K
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Messenger, Kristen M
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
  • Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Gilbertie, Jessica M
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Ellis, Ilene M
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Schnabel, Lauren V
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.

Grant Funding

  • K01 OD027037 / NIH HHS
  • T32 OD011130 / NIH HHS
  • T35 OD011070 / NIH HHS

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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